tbuckley/cabot-search huggingface dataset:
Refining the serum miR-371a-3p test for viable germ cell tumor detection: Identification and definition of an indeterminate range.
Authors: Aditya Bagrodia, John T. Lafin, Cinzia Scarpini, Bendu Konneh, Thomas Gerald, Michelle Nuno, Jin Piao, Anna Savelyeva, Liwei Jia, Sarah Murray, Yun Cheng, Vitaly Margulis, Solomon L. Woldu, Nicholas Coleman, James F. Amatruda, Lindsay Lindsay Frazier, Matthew Murray
Journal: Journal of Clinical Oncology (2023)

425 Background: Existing conventional serum tumor markers (STMs) exhibit moderate performance for the detection of germ cell tumors (GCTs). Circulating miR-371a-3p has excellent performance in the detection of viable (non-teratoma) GCT pre-orchiectomy; however, its ability to detect occult disease is understudied. We refine the serum miR-371a-3p assay and expand upon our previous experience in this setting. Methods: We compared performance of raw (Cq) and normalized (∆Cq, RQ) values from prior assays (n=93), and validated interlaboratory concordance by aliquot swapping. Revised assay performance was determined in a cohort of 32 patients suspected of occult retroperitoneal disease. Assay superiority was determined by comparing resulting receiver-operator characteristic (ROC) curves using the Delong method. Pairwise t-tests were used to test for interlaboratory concordance. We defined an indeterminate range as the mean of the low Cq peak from controls ± 2 SDs. Results: Performance was comparable when thresholding based on raw Cq vs. normalized values. Calculated sensitivity and specificity were both greater than 0.9 in all cases and did not change appreciably across any of the metrics tested. Interlaboratory concordance of miR-371a-3p was high, but reference genes miR-30b-5p and cel-miR-39-3p were discordant. We identified for the 1 st time an indeterminate range; Introduction of an indeterminate range of Cq 28-35 with a repeat run for any indeterminate improved assay accuracy from 0.84 to 0.92 in a group of patients suspected of occult GCT. Conclusions: We recommend that serum miR-371a-3p test protocols are updated to a) utilize threshold-based approaches using raw Cq values, b) continue to include an endogenous (e.g., miR-30b-5p) and exogenous non-human spike-in (e.g., cel-miR-39-3p) microRNA for quality control, and c) to re-run any sample with an indeterminate result.
Time to event following bacillus Calmette-Guerin therapy initiation in Medicare beneficiaries with intermediate- to high-risk non-muscle invasive bladder cancer, 2010-2019.
Authors: Allison A. Petrilla, Alison R. Silverstein, Anthony Eccleston, Allison Thompson, Julia Brinkmann, Temitope Bello, Jane Chang, Joseph C Cappelleri, Sanjana Chandrasekar, Amy L Schroeder
Journal: Journal of Clinical Oncology (2023)

473 Background: For patients with intermediate- to high-risk non-muscle invasive bladder cancer (NMIBC), standard of care includes transurethral resection (TURBT) followed by induction and maintenance intravesical immunotherapy with Bacillus Calmette-Guerin (BCG). This study describes characteristics and clinical outcomes of Medicare beneficiaries newly diagnosed with NMIBC who initiated BCG therapy following TURBT. Methods: Retrospective cohort study using Centers for Medicare and Medicaid-sourced Medicare Fee-for-Service medical/pharmacy claims (100% sample). Patient selection criteria: ≥1 bladder cancer diagnosis 2010-2019, no prior radiotherapy, systemic therapy, cystectomy, or metastasis in 6 months post-diagnosis, continuously enrolled in Medicare ≥12 months pre- and post-index (or death). Index date = date of first BCG instillation. A literature-based definition for adequate maintenance BCG defined adequate (≥7 instillations of BCG within 274 days of BCG initiation) and inadequate (remainder) BCG therapy for patient stratification. Events: time to BCG discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis. Provider access to BCG (due to supply shortage), patient tolerability, and NMIBC risk status are not captured in claims data. Results: Of 46,052 BCG-treated patients eligible for analysis, 19,859 (43.1%) received adequate BCG therapy. The two cohorts had similar baseline characteristics (Table) and median duration of follow up (46 months). Median (interquartile range [IQR]) time from NMIBC diagnosis to BCG initiation was 2.8 (8.2) months for adequate, 3.7 (14.4) months for inadequate BCG. Time from BCG initiation to discontinuation, radical cystectomy, systemic therapy, radiation, and metastasis are reported in the table. Conclusions: Between 2010 and 2019, 57% of Medicare patients initiating BCG following diagnosis of NMIBC and TURBT may not have received adequate BCG therapy. Patients with inadequate BCG therapy had numerically shorter time to radical cystectomy, systemic therapy, radiation, and metastasis than those with adequate BCG therapy. Characteristics &amp; Outcomes by Cohort. [Table: see text]
Characterization of ctDNA findings at the end of life in patients with prostate cancer.
Authors: Kanika Gupta, Sydney Caputo, Crystal Casado, Albert Jang, Patrick L Sweeney, Sree M Lanka, Olivia Pocha, Maddie Hawkins, Alexandra Lieberman, Jennifer Schwartz, Patrick Miller, Ellen B. Jaeger, Pedro C. Barata, Jodi Lyn Layton, Brian E. Lewis, Elisa M. Ledet, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2023)

230 Background: Somatic alterations change over time in response to treatment and disease progression in patients with prostate cancer (PCa). We report ctDNA findings of patients who died from PCa within 3 months of a ctDNA assessment to better characterize patients with fatal disease. Methods: A total of 118 patients with PCa specific mortality who had been treated at Tulane Cancer Center and had ctDNA assessments between 2015 and 2022. The ctDNA was assessed by Guardant360 (Guardent Health, Inc) assays to identify alterations, pathogenic mutations and/or copy number alterations (CNAs) in cancer-related genes. Clinical annotation including treatment history, genetics, and staging were also obtained. Statistical analyses included Fischer’s Exact and Wilcoxon tests. Results: Of the 118 patients with PCa specific mortality, 42% (49/118) had a ctDNA assessment &lt;3 months from death. Of 49 CRPC patients tested within 3 months of death, the median number of life extending therapies (LET) at death was 5 (2-9). Patients had a median of 2 (0-6) LET prior to first ctDNA screening and 3 (0-7) LET in between first and last ctDNA assessment. Of the total gene alterations detected on ctDNA analysis, within 3 months of death, the most common alterations detected were 65.3% (32/49) TP53, 44.9% (22/49) AR, 28.6% (14/49) EGFR, 24.5% (12/49) PIK3CA, 22.4% (11/49) MYC, and 20.4% (10/49) CDK6. In a paired analysis(n= 45) of first and last ctDNA screening, AR (OR= 2.35, 95% C.I. (0.99, 5.62), p= 0.05), CDK6 (OR= 4.00, 95% C.I. (1.02, 15.68), p= 0.04), FGFR1 (OR= 9.51, 95% C.I. (1.14, 79.61), p= 0.03), and EGFR (OR= 9.71, 95% C.I. (2.06, 45.83), p= 0.0009) were significantly more likely to be detected in ctDNA screening within 3 months of death. In addition, ctDNA alterations in general were significantly more likely to be detected at the end-of-life (p=&lt; 0.00001). Other ctDNA gene mutations did not have statistically significant increases. Conclusions: An analysis of patients with PCa mortality showed most frequent gene alterations in TP53, AR, EGFR, PIK3CA, MYC, and CDK6. When comparing patients’ first and last ctDNA, alterations were significantly more likely by time of death in AR, CDK6, EGFR, FGFR and there was a significant increase in overall detection of somatic alterations in ctDNA. These analyses are limited to the genes assessed on the ctDNA panel and may or may not reflect all of the functionally relevant alterations. Further the CNAs reported herein may reflect broad genomic changes rather than specific gene alterations.
Determining the impact of genomic classifier testing on patient-reported quality of life after prostatectomy: Results from the G-MINOR randomized trial.
Authors: Udit Singhal, Stephanie Daignault-Newton, Rodney Dunn, Daniel Eidelberg Spratt, Linda Okoth, Felix Y Feng, Anna Johnson, Brian R Lane, Susan Linsell, Ghani Khurshid, Rohit Mehra, Elai Davicioni, Thomas Maatman, Frank Burks, Paul Rodriguez, Eduardo Kleer, Richard Sarle, David Christopher Miller, Michael L. Cher, Todd Matthew Morgan
Journal: Journal of Clinical Oncology (2023)

345 Background: Decipher is a tissue-based genomic classifier (GC) developed and validated in the post-radical prostatectomy (RP) setting to help guide adjuvant treatment decisions for prostate cancer (PCa). We conducted the first prospective, randomized trial assessing the impact of GC testing on adjuvant therapy use. Here, we determine the impact of GC testing on patient reported (PRO) quality of life outcomes (QoL) in men at high-risk of post-RP recurrence. Methods: The G-MINOR trial is a prospective, unblinded, randomized trial which enrolled 356 patients from 12 centers in the Michigan Urological Surgery Improvement Collaborative (MUSIC). Patients were enrolled between Aug 2016-July 2018. Eligible patients had undergone RP within 9 months of enrollment, had pT3-4 disease and/or positive surgical margins, and a post-RP PSA &lt;0.1ng/mL. Patients were assigned to either the GC or usual-care (UC) group using cluster-crossover block randomization assignments. Evaluable patients (338) were followed for at least 18 months. PROs were obtained using the Expanded Prostate Cancer Index Composite (EPIC-26) survey at baseline (before RP), 3, 6, 12, and 24 months after RP. Results: A total of 226/338 evaluable men (67%) had PRO data for this analysis (116 UC arm/110 GC arm). Median age was 65 years. Of the 226 men included in the PRO analysis, a total of 23 (9 UC arm/14 GC arm) had adjuvant treatment (p = 0.22). At 12 months follow-up, those in the GC arm had no significant change in adjusted mean difference in domain score from baseline compared to those in the UC arm for urinary irritative (UIR) function (1.0, 95% CI [-2.9– 4.9], p=0.6), urinary incontinence (UI) (0.8, 95% CI [-5.1– 6.7], p=0.8), or sexual function (SF) (0.5, 95% CI [-6.9– 7.9], p=0.9). This remained true at 24 months for all three domains [UIR; (2.3, 95% CI [-2.1– 6.6], p=0.3)], [UI; (-0.3, 95% CI [-7.3– 6.7], p=0.9)], [SF; (1.5, 95% CI [-6.8– 9.7], p=0.7)]. Conclusions: In the first ever randomized trial testing the clinical utility of a GC test in localized PCa, longitudinal patient reported QOL outcomes were not significantly different between men who underwent risk stratification with or without Decipher. Clinical trial information: NCT02783950 .
Updated experience on PSMA PET/CT for recurrent prostate cancer in a high-volume Brazilian center.
Authors: Dr. Paulo Sergio Lages, Luciano Monteiro do Prado Junior, Leonardo Fonseca Monteiro do Prado, Bruno Carvalho Oliveira, Renato Ramos Barra, Michelle Silva Barbosa, Daniel Vargas Pivato de Almeida
Journal: Journal of Clinical Oncology (2023)

50 Background: PSMA PET/CT scan ( 68 Ga-PSMA PET/CT) has emerged as a highly accurate tool when assessing disease staging both for newly diagnosed localized high-risk prostate cancer and for recurrent disease, with treatment plan modification in up to two-thirds of patients. Methods: We retrospectively reviewed the PSMA PET/CT scans results of patients undergoing the exam in all disease stages in a single institution in Brasilia, Brazil, between October 2015 and July 2022 and correlated clinicopathological information with test results for those in the recurrent disease setting. Results: Overall, more than 2,500 PSMA PET-CT scans were performed during the selected time interval. Any clinicopathological information was available for 648 patients, of whom 586 underwent the test in the setting of recurrent disease following treatment of primary disease. Positive results were found in 400 studies, with a median PSA level of 1.035 ng/mL (IQR 0.3–3.5) and most prevalent Gleason score of 7 (3+4). Metastatic disease was found in 26.2% of patients with a median PSA level of 4.61 ng/mL. Conclusions: A positive correlation between both PSA level and Gleason grade and the positivity rate of PSMA PET/CT was found in this large dataset, confirming the findings previously demonstrated in a prior presentation of our database. This result reinforces the importance of including more sensitive image methods when staging recurrent prostate cancer for the early detection of metastatic disease and adequate treatment planning. [Table: see text]
Evaluation of eligibility criteria in contemporary renal cell carcinoma based on ASCO-FCR recommendations.
Authors: Sweta R. Prajapati, Matthew I. Feng, Daniela V. Castro, Kyle O. Lee, Elyse H. Chan, Ishaan Sehgal, Jalen Patel, Anna O'Dell, Zeynep Busra Zengin, Xiaochen Li, Alex Chehrazi-Raffle, Nazli Dizman, Abhishek Tripathi, Adam Rock, Sandy Liu, Benjamin D. Mercier, Luis A Meza, Errol James Philip, Tanya B. Dorff, Sumanta Monty Pal
Journal: Journal of Clinical Oncology (2023)

612 Background: A consensus statement from the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FCR) collaboration highlights the importance of expanding eligibility criteria in cancer trials to more accurately reflect the real-world population (Kim et al., Clin Cancer Res 2021). We sought to characterize use of overly restrictive eligibility criteria in renal cell carcinoma (RCC) trials in the context of ASCO-FCR recommendations. Methods: Studies containing the MeSH terms “(metastatic OR advanced OR stage IV or unresectable) AND (kidney cancer OR renal cell carcinoma OR renal cell cancer)” from June 30, 2012 to June 30, 2022 were identified on the ClinicalTrials.gov platform. Our search query’s inclusion criteria identified international studies examining adult patients aged ≥ 18 in phase I-III trials. Exclusion criteria comprised pan-cancer studies, trials involving localized treatments, radiation therapy, and prognostic tools. Descriptive statistics were used to characterize the frequency of restrictive eligibility criteria across studies, while Fisher’s exact test or chi-square test were utilized to determine the association between treatment type and exclusion criteria. Results: The content of 423 RCC trials were analyzed, of which 112 (26.5%) had adequate data available. 48 (42.9%), 44 (39.3%) and 18 (16.1%) studies examined combination therapy, targeted therapy, and immunotherapy, respectively. The presence of HIV positivity, HBV/HCV positivity, brain metastases, and concurrent malignancies accounted for the most frequently cited exclusionary criteria, seen in 83/112 (74.1%), 60/112 (53.6%), 37/112 (33.0%), and 9/112 (8.0%) studies respectively. Differences in the use of HIV positivity (p&lt;0.001) and HBV/HCV positivity (p&lt;0.001) as eligibility criteria were observed across classes of therapy (see Table). Conclusions: A significant proportion of RCC studies utilize overly restrictive eligibility criteria as highlighted by the ASCO-FCR joint statement. Appropriate broadening of eligibility criteria to incorporate patient populations mirroring a real-world setting will provide more useful data going forward. [Table: see text]
Cabozantinib in combination with atezolizumab in non-clear cell renal cell carcinoma: Extended follow-up results of cohort 10 of the COSMIC-021 study.
Authors: Bradley Alexander McGregor, Neeraj Agarwal, Cristina Suárez, Kai Tsao, William Kevin Kelly, Lance C. Pagliaro, Ulka N. Vaishampayan, Daniel Castellano, Yohann Loriot, Fiona Xu, Lana Andrianova, Ramu Sudhagoni, Toni K. Choueiri, Sumanta Monty Pal
Journal: Journal of Clinical Oncology (2023)

684 Background: In the COSMIC-021 phase 1b study (NCT03170960) evaluating cabozantinib plus atezolizumab in advanced solid tumors, this combination therapy demonstrated encouraging clinical activity in patients with advanced non-clear cell renal cell carcinoma (nccRCC) with a median follow-up of 13 mo (Pal. JCO 2021). Results after extended follow-up in nccRCC are presented. Methods: Patients with advanced nccRCC and ECOG PS 0/1 who had ≤1 prior VEGFR-targeting tyrosine kinase inhibitor (TKI) were eligible. Prior treatment with TKIs targeting MET or immune checkpoint inhibitors was not allowed. Patients received cabozantinib 40 mg PO QD plus atezolizumab 1200 mg IV Q3W until unacceptable toxicity or progression; dose reductions of cabozantinib (40 mg QD to 20 mg QD, then to 20 mg QOD) were permitted to manage adverse events. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by the investigator; other endpoints included safety, duration of response (DOR), PFS, and OS. Results: The study enrolled 32 patients with nccRCC (2 from dose escalation phase, and 30 from expansion phase of the study): median age, 62 y; male, 81%; ECOG PS 0/1, 75%/25%; histology, papillary/chromophobe/clear cell/other, 47%/28%/3%/22%; sarcomatoid feature, 13%; IMDC risk favorable/intermediate/poor, 50%/41%/9%; ≥3 tumor sites, 56%; tumor sites, lung/kidney/bone/liver, 50%/25%/16%/16%; prior nephrectomy, 63%; prior VEGFR TKI, 22%; 0/1 lines of prior therapy (locally advanced/metastatic setting), 81%/19%. As of July 21, 2022, median follow-up was 37.2 mo (range 32.1–58.5) with 5 (16%) patients remaining on study treatment. ORR by investigator was 31% (all PRs) and disease control rate was 94% (Table); median DOR was 8.1 mo. Median PFS was 9.3 mo (95% CI 5.5–12.3), and median OS was not reached (95% CI 23.0–NE). PFS and OS estimates at 12 mo were 34% and 84%, respectively; 24-mo estimates were 6% and 70%. Treatment-related AEs occurred in 97% (grade 3/4, 53%); the most common AEs included diarrhea (69%), palmar-plantar erythrodysesthesia (50%), fatigue (44%), dysgeusia (41%), hypertension (31%) and nausea (31%). One grade 5 treatment-related AE of pulmonary hemorrhage occurred. Treatment-related AEs leading to discontinuation of both study treatments occurred in 13% of patients. Conclusions: Extended 3-year follow-up reinforces the encouraging clinical activity of cabozantinib plus atezolizumab in advanced nccRCC with a manageable safety profile. Clinical trial information: NCT03170960 . [Table: see text]
Evaluating technical feasibility of a urine cell-free DNA (cfDNA) NGS assay for identifying biomarkers in bladder cancer.
Authors: Il-Jin Kim, Michelle Quiroz, Zhixin Zhao, Wei Mo, Tiantian Zheng, Amy Wang, Usha Singh, Neil Beeharry, Denis Smirnov, Songbai Wang, Renee Tate, Tom Zhang, Fang Liu, Seema Hanumanthe, Binggang Xiang, Shujun Luo, Alexander Kuklin, Ralph M. Wirtz, Pan Du, Shidong Jia
Journal: Journal of Clinical Oncology (2023)

565 Background: Bladder cancer is one of the most common cancers worldwide. In 2022, about 81,000 people were diagnosed with this disease and 17,000 died from it (www.cancer.org). Despite significant breakthroughs in targeted medicines (i.e., Erdafitinib, FGFR2/3 kinase inhibitor) and clinical care over the past decade, non-invasive molecular testing remains an unmet clinical need for the treatment of bladder cancer patients. By contrasting the results with those from the FDA-approved tissue-based CDx assay, we assess the clinical utility of a urine NGS assay for identifying biomarkers, including mutations from FGFR genes. Methods: Paired urine and tissue samples were collected from 107 (muscle and non-muscle invasive) bladder cancer patients from the Bladder BRIDGister clinical trial in Germany. Tissue specimens were analyzed using the FDA approved Qiagen therascreen FGFR RGQ RT-PCR kit while matched urine samples were processed using the PredicineCARE urine (cell-free DNA) cfDNA NGS assay with detection sensitivity of 0.3% (0.1% for hotspot mutations). One hundred seven bladder cancer urine cfDNA NGS and tissue RT-PCR results were analyzed to determine the concordance (PPA and NPA) between these two assays. A smaller sample set was also used to compare tissue NGS to therascreen RT-PCR and tissue NGS to urine cfDNA NGS. A subset of discordant mutations were additionally validated by ddPCR. Results: For the concordance analysis between PredicineCARE Urine cfDNA NGS and therascreen tissue RT-PCR assay of 107 samples, PPA was 100% (20/20, 95% CI: 83.2-100) and NPA was 94.1% (48/51, 95% CI: 83.8-98.8). Three discrepant samples (tissue FGFR negative but urine positive for FGFR genes) were further analyzed by independent orthogonal ddPCR (Bio-Rad ddPCR Mutation Detection Assay). All tissue FGFR negative but urine positive samples were confirmed positive by ddPCR. PPA and NPA between PredicineCARE Urine cfDNA and Tissue NGS were 100% (19/19, 95% CI: 82.4-100) and 94.2% (49/52, 95% CI: 84.1-98.8) respectively. PPA and NPA between PredicineCARE Tissue NGS and Therascreen FGFR RGQ RT-PCR kit were both &gt; 95%. Conclusions: High concordance between FGFR alterations detected with an FDA approved tissue CDx and urine cfDNA NGS assay demonstrates that the PredicineCARE urine cfDNA NGS assay may represent a novel, accurate, and non-invasive clinical application for molecular diagnostic testing to identify biomarkers in bladder cancer.
A phase 2 study of ibrutinib as neoadjuvant therapy in patients with localized prostate cancer.
Authors: Cayce Ben Nawaf, Bo Peng, Melissa Andrea Reimers, Cody Weimholt, Kathryn Slane, Peter John Oppelt, Jason Frankel, Robert S. Figenshau, Eric H Kim, Gerald L. Andriole, Lawrence Fong, Russell Kent Pachynski
Journal: Journal of Clinical Oncology (2023)

387 Background: Treatment of localized prostate cancer (PCa) with surgery or radiotherapy remains suboptimal with failure rates of 35-40%. Bruton’s Tyrosine Kinase (BTK) is seen elevated in PCa tissues compared to normal prostate tissue. Malignant B-cell density has been correlated with higher risk of aggressive PCa and mitigating that through the BTK has been proposed in mouse models. Ibrutinib is a potent BTK inhibitor which targets B-cell signaling pathways, has an established safety profile, and has been shown to inhibit in vivo prostate tumor growth pre-clinically. Therefore, we hypothesized that ibrutinib will augment anti-tumor immune responses through inhibiting tumor-intrinsic growth via blocking BTK B-cell signaling pathways, while also inducing favorable T-cell profiles in localized PCa. Methods: We performed a neoadjuvant clinical trial (NCT02643667) studying ibrutinib in PCa. Eligible patients had localized PCa with no prior treatment, and deemed suitable for undergoing a radical prostatectomy. Patients received 840mg/day oral ibrutinib for 28 days followed by a radical prostatectomy 7-12 days later. Patients were assessed 4 weeks after surgery. The primary objectives are to assess safety of ibrutinib and characterize B and T cell infiltration. Correlative pre- and post- treatment tissue and blood samples were collected; BTK and PD-L1 expression in tumor and immune-infiltrating immune cells will be examined, and BCR and TCR clonality and diversity will be evaluated. Results: 22 patients were registered and underwent treatment to date. 4 patients had early termination of ibrutinib treatment with 3 due to adverse effects and 1 due to discovery of surgically unresectable disease. A total of 21 of 22 patients received radical prostatectomies. There were no intra-operative complications attributed to ibrutinib. The treatment was generally well tolerated with 7.1% grade 3 treatment related adverse effects. 2% experienced a grade 4 treatment adverse effects of hepatic dysfunction. The most common grade 1-2 adverse effects were diarrhea (8.2%), fatigue (7.1%), and anemia (6.1%). The median follow-up time was 23.9 months. Median overall survival and median failure free survival have not been reached and the two-year milestone is 100%. Sample collection is complete and immune correlative analyses are ongoing. Safety/tolerability, clinical outcomes, and preliminary correlative data will be reported. Conclusions: This is the first clinical trial of ibrutinib in PCa, and lays the foundation for larger future studies. Clinical trial information: NCT02643667 .